17-alkoxy-1, 3, 5(10)-estratrien-3, 16-diols and the production thereof



July 12, 1960 M. N. HUFFMAN 2,945,048

17-ALKOXY-l ,a s 10 )-ESTRATRIEN-3, l6-DIOLS AND THE PRODUCTION THEREOF Filed April 14. 1958 ocH NO 8H4 ocH cw OH OH H0 1 HO OAc AcO

INVENT OR.

MAX N. HUFFMAN a ATTORNEYS 1'7-AILKOXY-1,3,'5(10)-ESIRA'IRIEN-3,16-DIOLS AND THE PRODUCTION THEREOF Max N. Huffman, Colorado Springs, 'Colo., assignor to 'Lasdon Foundation, Inc, Yonkers, N.Y., a corporation of Delaware Filed Apr. 1-4, 1958, Ser. No. 728,210

7 Claims. on. 260 -3975) wherein R is a lower alkyl radical containing 1 to 5 carbon atoms and X is hydrogen or an acyl radical containing 1 to 18 carbon atoms. p p In the foregoing compounds the radical R represents alkyl'radicals such as methyl, ethyl, propyl, isopropyl,

butyl, sec-butyl, isobutyl, amyl, sec-amyl, and isoamyl.

The acyl radicals represented by X' include alkanoyl radicals such as acetyl, propionyl, butyryl, pahjnityl, stearyl and the like, as well as benzoyl, toluyl, naphthoyl and similar aromatic acyl radicals.

The compounds of this invention are estrogen derivatives which have the valuable property of stimulating the reticuloendothelial system without exhibiting estrogenic activity. For instance, estriol exhibits estrogenic actiwty in rats at a dosage of micrograms subcutaneously or orally, but the compounds of this invention show only the slight estrogenic activity at much higher dosages.

The reticuloendothelial system plays an important role in cholesterol metabolism. Cholesterol-containing macromolecular aggregates appear to be phagocytosed by cells of the reticuloendothelial system. Stimulation of the reticuloendothelial system will accelerate the reduction of blood cholesterol levels. It has beenobserved that premenopausal women are virtually immune from coronary thrombosis and these observations led to the study of the effect of certain estrogens in experimental and clinical atherosclerosis. These studies indicate that certain estrogens cause a clinical improvement, as well as a reversion toward normal of the blood lipid picture'in' hypercholesterolemic individuals. On the basis of such studies 'it has been concluded that the estrogens may have a useful role in therapy or prophylaxis of disorders associated with abnormal concentrations of cholesterol in the blood and that the efficacy of these substances may be due to their stimulating effect upon the reticuloendothelial system. A major limiting factor in the clinical use of estrogens lies in their concomitant sexual eifect. Therefore, it is desirable to produce steroids having a stimulating effect on the reticuloendothelial system without the undesired sexual activity.

It is an object of this invention to provide steroids which stimulate the reticuloendothelial system which have negligible estrogenic or other sexual effect. It is another producing such steroids. An additional object is to provide novel steroids having desirable physiological properties. A further object is to provide new and useful 17-alkoxy l,3,5(10) estratrien 3,16 diol compounds. These and other objects will be apparent from and are achieved in accordance with the following disclosure taken in conjunction with the attached drawing which forms a part hereof.

'In the single sheet of drawing there is illustrated a process diagram of the production of 17 beta-methoxy- 1,3,5(10)-estratrien-3,l6 beta-diol ('III) and 17 beta-; methoxy-l,3,5(l0)-estratrien-3,16 alpha-diol (V) starting with 16-keto estradiol (1). The latter is methylated with dimethyl sulfate or similar methylating agent in the presence of aqueous alkali and a mixture of 1'6-keto estradiol-l7-methyl ether (II) and the corresponding 3,17-

dimethyl ether is formed. The monomethyl ether (11) can be separated from the dimethyl ether by proper'adjustment of the pH of the solution. (H) can then be reduced; with an alkali metal borohydrid'e or similar reagent'to the corresponding 16 beta-o1 compound (III).

By reduction of (II) with sodium and a lower alcohol (containing 1 to 5 carbon atoms) the corresponding 16 alpha-o1 epimer (V) can be produced. In order to purify (HI) it is convenient to react it with an acetylation agent to produce the. diacetate (IV) which can be purified readily and then hydrolyzed to 17 beta-methoxy-1,3,5

( l0)-estratrien-3,16 beta-diol (HI) The 17-a1koxy-1,3,5 10) -estratrien-3,16-'diols sented by the structural formula given above'are useful .medicinal agents .by' virtue of their property of stimuteriosclerosis, coronary thrombosis and the like.

lating the reticuloendothelial system of animals and humans, thereby aiding in the therapy or prophylaxis of disorders associated with abnormal concentrations of cholesteriol in the bloodstream, such as atherosclerosis, ar-

The

' compounds of this invention can be administered by activity and, therefore, appear to be without undesired" side effectsor toxicity. For instance, 17 beta-methoxyl,3,5(10)-estratrien3,16 beta-diol (III) when injected in adrenalectomized mice at a dosage of approximately 1 object of this invention to provide eflicient methods for milligram per kilogram produces a 26% increase in the white blood cell count, evidencing stimulation of the reticuloendothelial system, within 3 hours. At that dosage level no more than a slight estrogenic effect is observed.

The invention is disclosed in further detail by the means of the following examples which are provided for purposes of illustration only and which are not to be construed as limiting the scope of the invention. It will be appreciated by those skilled in the art that numerous modifications 'in synthetic procedures may be adopted without departing from this invention, such as the use of equivalent solvents, reagents, conditions and the like.

EXAMPLE 1 17 beta-methoxy-1,3,5 (10) -estratrien-3-0l-16-0ne To a solution of 4 grams of l6-ketoestradiol (I) and 2400 ml. of 0.5 N lithium hydroxide solution was added 32 ml. of dimethyl sulfate and the mixture was shaken for 30 minutes at room temperature. Then 28 ml. of additional dimethyl sulfate were added and the shaking con tinued for 30 minutes longer. Then the mixture was allowed to stand for about 15 hours at room temperature after which it was filtered to remove a precipitate of l6-ketoestradiol dimethyl ether. The filtrate was treated with solid carbon dioxide until the pH was re- Patented July 12, 1360 repre- 3 duced to 7.0-7.5 and then extracted with 2 liters of ether. The ether solution was washed with aliter of 3% sodium bicarbonate solution and with a liter of water. The ethereal solution Was then evaporated to dryness on, 5 steam bath and theresidpe of precipitate I Weig n'g 720mg. was dried at 35 C; Th pleases 16 ketoestraldiol 17-methyl ether (11); It was dissolved in" 109' rill: of manners-eaten with activatedcha'rcoal, filtered and the filtrate evaporated until crystallization 06c fed; The crystals of l6-ketoestradiol-17-n1e'myl other (1 1) were collected on a filter, washed witli- 66% methanol at room temperature. Zane-v from 80% aqueeiie methanol; there were obtained c fi i of lo ketoestradiol-17-methyl einer iiieltiiig at 271472 C." (with decomposition).

EXAMPLE 2 17 be'td-fiiethbbcY-IJQS (1-0')-e'st riitrieii-3,16 b'et a-dibl To a solution of 1.01 grams of 16-ketoestradiol-17- methyl ether (II) in 800 m1. er 0.2 N potassium hydr'oxid'e solution was added 500 mg. of potassium borohydride, the temperature of the solution being maintained at 0 to 2C. The reaction mixture was allowed to stand at tee temperature for a few hours and then allowed to 20 ml. of.

warm up to room temperature over night. acetone were added to destroy the excess of potassium b'o'rohydride andthen' the pH of the solution was reduced to 3 with concentrated hydrochloric acid and the resulting solution was refrigerated for about 24 hours. The pre= cipitate of 17' beta-methoXy 1,-3,5'(l0)-estratrien 3,16 beta-diol (III) was removed, washed well with water and dried at 35" C. It'was recrystallized from 55% methanol and there Was obtained 450 mg. of impure product melting not sharply at around 245 C. This material was purified by the procedure of Example 3.

EXAMPLE 3 The 450 mgof crude 17-methoXy-1,3,'5(10)-estratrien- 3,16 beta-'diol (111-) from Example 2 wasdissolved in 50 ml; of'pyridine and treated with 50 ml. of acetic anhydride. The resulting solution was swirled at room temperature and allowed to stand over night. The next day a liter of ice water was added to the solution and the mix-j ture was refrigerated; A precipitate of 17-methoXy-1,3,5 (10)-estratrien-3,16 beta-diol diaceta'te (IV) was collected on a filter, washed well with water and dried. The yield was 590 mg. of compound melting at 119-120 C. On further recrystallization the melting point of this product can be increased to 12'0.5121 C.

By analogous procedures using equivalent quantities of butyryl chloride, benzoyl chloride; palmitic anhydride, stearyl chloride or beta-naphthoyl chloride in lieu of acetic anhydride, there are produced 17-methoxy-1,3,5 (10)- estratrien-3,16 beta-diol dibutyrate, dibenzoate; di-

palmitate,;distearate or din'aphthoate.

The 17 beta-methoxy-1,3.5(l0)-estratrien-3,16 betadiol diacetate (IV) preparedabove was dissolved in 320 ml. of hot methanol to which was added 160 m1. of 2.0 N sodium hydroxide solution: The resulting solu- On further recrystalli- 244-245 C. and amounted t0'270 mg.

EXAMPLE 4 17 b'tZz-iizethoxy-Lidfld)-estratrin=3,ld alpha-dial To a solutionof 500 mg. of 16-ketoestradiol-17-methyl ether 11 in- 100111. of n= iapy1e1eene1 heated to reflux was added 3.3 grams ofsodium in small pieces over a period of 75 minutes. The reaction mixture was diluted with 1 liter of ice water and refrigerated over n ght.

- The precipitate of 17 beta-methoxy-1,3,5(10),-estratrien- 3,l6 alpha-diol (Vl collected on a filter, washed Wellwith wafefiafid dried. I

What. is cleaned as new and is desired to be secured by Letters Patent efihe United States is:

1. A compound of the formula wherein a is a lower alkyl radical contailiing 1 to 5 carbon atoms and X is a member of the group consisting of hydrogen afid hydrocarbon acylradicals containing 1 to l8 caibon atoms.

2. 17 beta-alkoXyI,3,5(lO)'-estratrien-3,l6-d'io1where- A in the alkoxy group contains 1 to 5 carbon atoms.

3. 17 beta=rnethoXy-'1,3,5(10)estratrien-3,16 beta-diol.

4. 17 beta-methoXy-1,-3,5(10)-estratrie1i-3,16 alphadiol.

5. 17 beta-methoxy-l,3,5(10)-estratfien-3,16-dio1 diacetate.

. 6. A method of producing 17 beta-methoxy-l,3,5(l0)- es'ti'at'rien-llo alpha-diol which comprises reacting 16- keto-estradiol-l7-methyl ether with a reducing agent comprising an alkali metal and a lower alkanol to reduce the 16 l eto radical to a 16 alpha-hydroxyl radical.

7. The method of claim 6 wherein the reducing agent is sodium and propanol.

References Cited in the file of this patent UNITED STATES PATENTS 238L073 Mie s'cher et a1. Aug. 7, 1945 2,534,271 Hartman Peas, 1952 3,705,239 i eman Mar. 29, 1955 2,744,120 Fried et a1 May 1, 1956 2,779,773 Hufim'an Ian. 29, 1957 

1. A COMPOUND OF THE FORMULA 